J. Am. Chem. SOC.1993,115, 3997-4006
3997
Syntheses and Optical Resolution of Calix[4]arenes with Molecular Asymmetry. Systematic Classification of All Possible Chiral Isomers Derivable from Calix[ 41arene Koji Iwamoto, Hiroyasu Shimizu, Koji Araki, and Seiji Shinkai' Contribution from the Department of Organic Synthesis, Faculty of Engineering, Kyushu University, Fukuoka 81 2, Japan Received December 21, 1992
Abstract: All possible chiral isomers that can be derived from calix[4]arene by modification of the OH groups were systematically classified. Molecular asymmetry can be generated not only by different substituents but also by conformational isomerism. The numbers of chiral isomers are 24 for tetra-0-substituted calix[4]arenes, 10 for tri0-substituted calix[4]arenes, 3 for di-0-substituted calix[4]arenes, and 0 for mono-0-substituted calix[4]arenes. This implies that calix[4]arene is a useful building block for the design of novel asymmetric ring structures. In order to demonstrate asymmetry in these chiral calix[4]arenes, we synthesized several tetra-, tri-, and di-0-substituted calix[4]arenes by using the metal template method, the stepwise synthesis method, the protection4eprotection method, etc., which were developed in efforts directed toward regioselective 0-alkylation and control of conformational isomerism in calix[4]arenes. Finally, we succeeded in complete optical resolution of chiral calix[4]arenes by an HPLC method using a chiral-packed column or by the formation of diastereomers with the (-)-menthoxyacetyl group. This article thus contains all of the molecular design concepts, syntheses, and optical resolutions of chiral calix[4]arenes.
Introduction Calix[n]arenes are cyclic, cavity-shaped oligomers made up of phenol and formaldehyde building block~.I-~ Cyclodextrins have a similar cavity-shaped architecture and are known to serve as receptors with chiral recognition ability imparted by the chiral D-glucose ~ubunits."~One may expect similar chiral recognition ability with calix[n]arenes if they are appropriately modified withchiral substituents. At the preliminary stages ofthis research, chiral substituents were introduced directly into the calix[n]arene framework,s-10and in some cases partially asymmetric molecular recognition was attained.9,10 We considered, however, that if molecular asymmetry could be directly generated from calix[4]arene, it would be more interesting and more fruitful not only from a stereochemical viewpoint but also from the viewpoint of chiral recognition. It was expected that if substituents are introduced into a calix[4]arene ring in an asymmetric manner, the product calix[4]arene would have no plane of symmetry. For example, calix[4]arenes with four different substituents should result in a pair of enantiomers. It is known, however, that in OH-unmodified calix[4]arenes ring inversion takes place at a speed comparable with theNMRtimescale.2J1J2 Thisimplies that opticalresolution can be effected only when the ring inversion which causes (1) Gutsche, C. D. Prog. Macrocycl. Chem. 1987, 3, 93. (2) Gutsche, C. D. In Calixarenes;Royal SocietyofChemistry: Cambridge, UK, 1989. (3) Gutsche, C. D.; Iqbal, M.; Nam, K. S.; See, K.; Alam, I. Pure Appl. chem. 1989, 60,483. (4) Breslow, R. Ace. Chem. Res. 1980, 13, 170. ( 5 ) Tabushi, I. Acc. Chem. Res. 1982, 15, 66. (6) Bender, M. L.;Komiyama, M. In Cyclodextrim Chemisfry; Springer-Verlag: New York, 1977. (7) D'Souza, V. T.; Bender, M. L. Acc. Chem. Res. 1987, 20, 146. (8) Muthukrishnan, R.; Gutsche, C. D. J. Org. Chem. 1979, 44, 3962. (9) (a) Shinkai, S.;Arimura, T.; Satoh, H.; Manabe, 0. J. Chem. SOC., Chem. Commun. 1987, 1495. (b) Arimura, T.; Edamitsu, S.; Shinkai, S.; Manabe, 0.;Muramatsu, T.; Tashiro, M. Chem. Lett. 1987, 2269. (10) Arimura, T.; Kawabata, H.; Mutsuda, T.; Muramatsu, T.; Satoh, H.; Fujio, K.; Manabe, 0.;Shinkai, S . J. Org. Chem. 1991, 56, 301. (1 1) Araki, K.; Shinkai, S.; Matuda, T. Chem. Letf. 1989, 581. (12) KBmmerer, H.; Happel, G.; Mathiasch, B. Makromol. Chem. 1981, 182, 1685.
racemization is sufficiently suppressed. Recently, Bdhmer et al.Ij-15 and Vicens et a1.16 synthesized calix[4]arenes in which the substituents were arranged asymmetrically on the benzene rings. However, no further reports have appeared on their efforts toward the optical resolution of these racemates. It is known that ring inversion can be readily inhibited by introducing substituents bulkier than an ethyl group onto the OH groups (e.g., by etherifi~ation).'~-~~ We previously attempted 0-propylation of a calix[4]arene asymmetrically substituted on the benzene ring to suppress the oxygen-through-the-annulus rotation and to obtain a pair of enantiomers for optical resolution.21-22However, suppression of the rotation by 0-substitution resulted in a number of conformational isomers (because of the combination of cone, partial cone, 1,Zalternate, and 1,3-alternate conformations with inversion of four inequivalent phenol units).*l,22 This result taught us to selectively synthesize and isolate, prior to optical resolution, a pair of enantiomers from themany possible isomers. After much trial and error, we finally found that the metal template effect is very useful for selective synthesis of one (13) Bohmer, V.; Merkel, L.; Kunz, U. J. Chem. SOC.,Chem. Commun. 1987, 52, 3200.
(14) Bohmer, V.; Marschollek, F.; Zetta, L.J. Org. Chem. 1987,52,3200. (15) Bohmer, V.; Wolff, A.; Vogt, W. J. Chem. SOC.,Chem. Commun. 1990, 968. (16) Casabianca, H.; Royer, J.; Satrallah, A,; Taty-C, A,; Vicens, J. Tetrahedron Lett. 1987, 28, 6595. (17) Araki, K.; Iwamoto, K.; Shinkai, S.; Matuda, T. Chem. Lett. 1989, 1747. (18) Iwamoto, K.; Araki, K.; Shinkai, S. Tefrahedron 1991, 47, 4325. (19) Iwamoto, K.; Araki, K.; Shinkai, S . J. Org. Chem. 1991, 56, 4955. (20) Conformational isomerism in calix[4]arenes and related compounds was also discussed by Reinhoudt et al., Ungaro et al., and Gutsche et al. (a) Groenen, L. C.; van Loon, J.-D.; Verboom, W.; Harkema, S.;Casnati, A,; Ungaro, R.; Pochini, A.; Ugozzoli, F.; Reinhoudt, D. N. J. Am. Chem. SOC. 1991, 113, 2385. (b) van Loon, J.-D.; Groenen, L. C.; Wijmenga, S. S.; Verboom, W.; Reinhoudt, D. N. J. Am. Chem. SOC.1991, 113, 2378. (c) Casnati, A.; Pochini, A.; Ungaro, R.; Cacciapagli, R.; Mandolini, L. J. Chem. SOC.,Chem. Commun. 1991, 2052. (d) Gutsche, C. D.; Bauer, L. J . Tefrahedron Left. 1981, 22, 4763. (e) Gutsche, C. D.; Bauer, L. J. J. Am. Chem. SOC.1985, 107, 6052. (21) Shinkai, S.; Arimura, T.; Kawabata, H.; Murakami, H.; Araki, K.; Iwamoto, K.; Matuda, T. J. Chem. SOC.,Chem. Commun. 1990, 1734. (22) Shinkai, S.;Arimura, T.; Kawabata, H.; Murakami, H.; Iwamoto, K. J. Chem. SOC.,Perkin Trans. 1 1991, 2429.
OOO2-7863/93/1515-3997$04.00/0 0 1993 American Chemical Society
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3998 J. Am. Chem. Soc., Vol. 115, No. 10, 1993
conformer (particularly the cone conformer).17-19 This breakthrough enabled us for the first time to synthesize a conformationally frxed, asymmetrically substituted calix[4]arene and to optically resolve the r a ~ e m a t e . ~ ~ , ~ ~ Throughout these studies, we were plagued by two difficult problems: (i) complicated conformational isomerism in calix[4]arenes and (ii) synthetic problems in calix[4]arenes asymmetrically substituted on the benzene moieties. It occurred to us that such complexity (i) might be rather useful in generating some new asymmetry on the calix[4]arene ring. For example, introduction of two different substituents may be enough to make the calix[4]arene ring chiral if one of them is inverted. The second difficulty may be resolved by introducing substituents onto the OH groups by a Williamson reaction instead of introducing them onto the benzene moieties. To further examine these ideas, introduction of different substituents onto the OH groups by a Williamson reaction was attempted, and the product calix [4]arenes were optically resolved by an HPLC method using a chiral-packed column or by the formation of diastereomers. On the basis of these studies, we can now systematically classify all possible "chiral" conformers derived from calix[4] arene.
Results and Discussion Classificationof All PossibleChiral Isomers. We now consider the 0-alkylation products of calix[4]arene. All possible conformational isomers for tetra-0-alkylation of calix[4]arene are summarized in Table I. In this table, A, B, C, and D denote 0-substituents, and shadowedcircles denote inverted phenol units; for example,
cone
partial-cone
cone
It is seen from Table I that, basically, one can synthesize 43 different calix [4]arene derivatives by tetra-0-alkylation. Among the four possible conformations, the partial cone, which is classified as the conformationwith the lowest symmetry, involves the largest number of 0-alkylation products (19 products). Assuming that these 0-substituents are bulky enough to inhibit oxygen-throughthe-annulus rotation, one can count 24 chiral 0-alkylation products, which are shown by an asterisk in Table I. Clearly, (23) Iwamoto, K.; Yanagi, A.; Arimura, T.; Matsuda,T.; Shinkai, S. Chem. Lett. 1990, 1901 (preliminary communication). (24) Optical resolutionof a tetra-0-substituted calix[4]arene using a similar method was recently reported: Pappalardo, S.; Caccamese, S.; Giunta, L. Tetrahedron Lett. 1991, 32, 7747.
asymmetry in the calix[4]arene ring can be generated not only by different substituents but also by inversion of the same kind of substituent. To demonstrate the asymmetry in these isomers, we have synthesized PraPraPrsBzla (Pr = n-propyl, Bzl = benzyl; cy and fl denote the direction of each phenol unit, that is, this compound has a partial-cone conformation with an inverted PrB group and is classified as AaAaABBa in Table I). In Table 11, we summarize all possible 0-alkylation products for tri-0-substituted calix[4]arenes (where H denotes the unsubstituted phenol unit). It is seen from Table I1 that 28 different calix [4]arene derivativesexist. In this table we can find 20 chiral compounds, which are shown by an asterisk. As we reported previously,18 the unsubstituted phenol unit in tri-0-substituted calix[4]arenes can rotate at room temperature, and the direction of the OH group is determined by the relative thermodynamic stability. Thus, several conformers become equivalent after the oxygen-through-the-annulus rotation of the OH group. The compounds enclosed in the shadowed frame in Table I1correspond to these conformers. For example, AaABABHa in the shadowed frame becomes equivalent to AaAaAsHa after rotation of the OH group. Hence, the actual number of chiral compounds is 10. Eight of the 10 products have a partial-cone conformation, and the two remaining products have a cone conformation. Of the possible structures, we synthesized PraPraBzlaHa (cone AaAaBaHa), BzlaPraPylaHa (cone AaBaCaHa; Pyl = 2-pyridylmethyl), PraPraPrsHa (partial cone AaAaABHa), and PraPrBBzlaHa (partial cone AaABBaHa). Similarly, we constructed Table 111,which includes 25 different di-0-substituted calix[4]arenes. In this table we can count 14 chiral products, but after the rotation of the two OH groups, only three inequivalent chiral products remain. Among them, we have synthesized PraPrsHaHs (1,3 alternate-AaAbHaHs). Lastly, it is impossible to conceive of any chiral compound from mono0-substituted calix[4]arenes. Syntheses of Chiral Calix[4]tarenes. In order to design asymmetrically substituted calix[4]arenes, Bijhmer et al.13-15 and Vicens et a1.16 modified the upper rim (Le., benzene rings). To introduce substituents onto the upper rim, one has to employ troublesome synthetic methods such as the Friedel-Crafts reaction, the Claisen rearrangement reaction, et^.^^-^^ We supposed that the same goal could be attained by simple 0-alkylation of the OH groups. Following the guidelines summarized in Tables 1-111, we decided to synthesize several calix[4]arenes (as in Schemes 1-111) with no plane of symmetry by 0-alkylation reactions and to demonstrate that these compounds actually behave as chiral compounds. Since the rotation is inhibited by substituents bulkier than the ethyl g r ~ u p , we ~~J~ employed Pr, Bzl, and Pyl groups. The starting material was 5,11,17,23-tetra-tert-butyIcalix[4]arene-25,26,27,28-tetrol(l). Treatment of 1with benzyl bromide (1.25 equiv) in toluene in the presence of NaH (1.14 equiv) gave the mono-0-benzylatedproduct (2) in 74% yield.I7J8J4 Treatment of 2 with propyl iodide (60 equiv) in THF/DMF (5:1, v/v) in the (25) Gutsche, C. D.; Lin, L.-G. Tetrahedron 1986, 42, 1633. (26) Gutsche, C. D.; Levine, J. A.; Sujeeth, P. K. J. Org. Chem. 1985,50, 5802. (27) Iwamoto, K.; Araki, K.; Fujimoto, H.; Shinkai, S.J. Chem. SOC., Perkin Trans. I 1992, 1885. (28) Gutsche, C. D.; Levine, J. A. J. Am. Chem. Soc. 1982,104, 2652. (29) van Loon, J.-D.; Arduini, A.; Verboom, W.; Ungaro, R.; van Hummel, G. J.; Harkema, S.; Reinhoudt, D. N. Tetrahedron Lett. 1989, 30, 2681. (30) van Loon, J.-D.; Arduini, A.; Coppi, L.; Verboom, W.; Pochini, A.; Ungaro, R.; Harkema, S.; Reinhoudt, D. N. J . Org. Chem. 1990,55,5639.
(31) Almi, M.; Arduini, A.; Casnati, A.; Pochini, A.; Ungaro, R. Tetrahedron 1989, 45, 2177. (32) Shinkai, S.; Nagasaki, T.; Iwamoto, K.; Ikeda, A.; He, G.-X.; Matsuda, T.; Iwamoto, M. Bull. Chem. SOC.Jpn. 1991, 64, 381. (33) Arimura, T.; Nagasaki, T.; Shinkai, S.; Manabe, 0. J. Org. Chem. 1989, 54, 3767.
(34) The mono-0-alkylation method of 1 was also reported by Ungaro et al.: Groenen, L. C.; Ruel, B. H.; Casnati, A.; Verboom, W.; Pochini, A.; Ungaro, R.; Reinhoudt, D. N. Tetrahedron 1991, 47, 8379.
J. Am. Chem, SOC.,Vol. 115, No. 10, 1993 3999
Syntheses and Optical Resolution of Calix[4]arenes Table I. All Possible Tetra-0-alkylation Products Derived from Calix[4]arenea number of different substituents
partial cone
1,2-alternate
1,3-alternate
1 AAAA
AAAB
2 J ABAB
AABB
4 ABCD a
Asterisks indicate chiral calix[4]arenes.
Table 11. All Possible Tri-0-alkylation Products Derived from Calix [4]arenea number of different substituents
cone
partial cone
1,2-alternate
13-alternate
1 AAAH
2
ABAH
3 ABCH a
@ @@ @
@@
Asterisks indicate chiral calix[4]arenes.
presence of NaH (12 equiv) gave PraPraPrOBzla with a partialcone conformation in 69% yield. It has been established that the final conformer distribution is strongly affected by the metal template effect; a cone results when the metal cation can act as a template, but conformers
other than the cone result when the metal cation cannot act as a template.l7-I9 One-step tetra-0-propylation of 1in the presence of N a H gives the cone and partial-cone conformers in approximately a 1:l ratio.17J9 This result suggests that the template effect of Na+ in the present reaction is not so strong, and PP-
Iwamoto et al.
4000 J. Am. Chem. SOC.,Vol. 115, No. 10, 1993 Table 111. All Possible Di-0-alkylation Products Derived from Calix[4]arene'
cone
number of diffenent substituents
1
1,2-alternate
partial cone
1,3-alternate
IAHAH
@
2
a
Asterisks indicate chiral calixt4larenes.
Scheme I OPr MejSlBr
OPr PraPraPrpBzla
OPr PraPraPrpHa
n-Prl THFlDMF
2 1-BU
1
n-PrBr -03
acetone
I
OPr PraPrPBzlaHa
PraPrPBzla with a partial-cone conformation is the main product. PraPraPrOBzla is an example of a tetra-0-substituted chiral product with two different substituents (Le., AaAaABBa;see Table I). The presence of at least three different substituents is a prerequisite in the realization of asymmetry on the calix[l]arene ring. In PraPraPr@Bzla,this requirement is satisfied by two different substituents and one inverted phenol unit. The benzyl group in PraPraPrBBzlawas then deprotected by Me3SiBr to give PruPraPrOHain 93% yield. This compound is an example of a tri-0-substituted chiral product with only one kind of substituent (Le., AaAaABHa;see Table 11). This result shows that the benzyl group can be used not only as a final substituent to generate asymmetry but also as a protecting group to synthesize less substituted chiral products. Treatment of 2 with propyl bromide (30 equiv) in acetone in the presence of Cs2C03(3 equiv) gave di-0-propylated PraPrflBzlaHa in 49% yield (Scheme I). We previously found that Cs+ ion is weakly bound to calix[4]arene derivatives and therefore
OH PraPrSHaHB
does not act as an effective template meta1.I7-l9 This nature of the Cs+ ion facilitates inversion of one phenol unit and immobilizes the conformation in the partial cone. PraPr@BzlaHais a chiral product with two different substituents and one inverted phenol unit (Le., AaAOBaHa;Table 11). Debenzylation of PraPrOBzlaHa with Me3SiBr gave PraPr@HaHBin 95% yield, which is classified as a di-0-substituted chiral product with only one kind of substituent (i.e., AaABHaHO; Table 111). Since inversion of the O H groups is allowed, this compound can adopt either the partialcone, 1,2-alternate, or 1,3-alternate conformation. Examination of the literature reveals that mono-, di-, and tri-0-substituted calix[4]arenes tend to adopt the conformation in which the OH groups can form as many intramolecular hydrogen bonds as p o ~ s i b l e . ~ *This J ~ rule predicts that this compound will favorably adopt a partial-cone conformation. However, the IH NMR spectrum in CDC13 indicates that this compound actually adopts a 1,3-alternate conformation. The reason for this observation is not well understood at present.
Syntheses and Optical Resolution of Calix[l]arenes
Scheme II
t
n.Prev PraPraPylaHa
4
BzIaPrnPylnHa
Scheme 111
5
The mono-0-Zpyridylmethyl derivative 3 can be synthesized from 1 and 2-(chloromethy1)pyridine hydrochloride (1.7 equiv) in DMF in the presence of Ba(OH)z.8HzO (2.85 equiv.) and BaO (2.85 equiv) (Scheme 11). The yield was 54%. We19921-23 and Gutsche et al.35 have found that Ba(OH)2 is a special base that stops the 0-alkylation reaction at the tri-0-substituted stage. We also found that the product tri-Osubstituted calix[4]arenes are only in the cone c~nformation.~~-*~-~~*~~ The novel behavior of Ba2+can be ascribed to suppression of the nucleophilicity of the phenoxide anion through the formation of ArO-Ba covalent bonds. This method is also useful for the stepwise introduction of substituents. Treatment of compound 3 with propyl bromide (10 equiv) in D M F in the presence of Ba(OH)zdH20 (4 equiv) and BaO (4 equiv) gave PraPraPylaHa with a cone conformation in 76% yield (Scheme 11). Similarly, treatment of compound 3 with benzyl chloride (1.1 5 equiv) in acetone in the presence of KzCO3 (10 equiv) followed by treatment with propyl bromide (10 equiv) in D M F in the presence of Ba(OH)z*8H20 (4 equiv) and BaO (4 equiv) gave BzlaPraPylaHa with a cone conformation. The yields for each step were 73% and 76%, respectively. When calix[4]arene adopts a cone conformation, the molecular asymmetry is realized for a minimum of three different substituents. The unsubstituted OH group can be counted as one substituent, so that one has to introduce at least two different substituents. Thus, PraPraRlaHa satisfies the minimum requirement for asymmetry (Le., AaAmBaHa;see Table 11). BzlaPraPylaHa also satisfies the requirement. These calix[4]arenes are classified as tri-0substituted chiral products with two or threedifferent substituents. The last example is PraBzlaHaHB (Scheme 111), which is classified as a di-0-substituted chiral product with two different substituents (Table 111). Treatment of 1 with benzyl bromide (4.5 equiv) in acetone in the presence of K2CO3 (1 1.4 equiv) gave di-0-benzylated 5 in 98% yield. It is known that to stop the 0-alkylation reaction at the mono-0-substituted stage is quite difficult.l'J As mentioned above for the synthesis of 2, the molar ratio of benzyl bromide:l is adjusted to 1.25 and that of NaH:1 to 1.14. In contrast, when the combination of K2CO3 as base and (35) Gutsche, C. D.; Dhawan, B.; Levine, J. A.; Hyun, K.; Bauer, L. J. Tetrahedron 1983, 39,409. (36) We later found that CaH shows a similar property in the reaction of calix[4]arene-25,26,27,28-tetroland ethyl bromoacetate: Shimizu, H.; Iwamoto, K.; Fujimoto, K.; Shinkai, S. Chem. krr. 1991, 2147.
J. Am. Chem. SOC., Vol. 115, No. 10, 1993 4001 acetone as solvent is used, most 0-alkylation reactions "automatically" stop at thedi-0-substituted stage, even in the presence of excess alkyl halide and excess base. The low reactivity is attributed to the conformational characteristics of di-0-substituted calix[4]arenes in which two unreacted OH groups are flattened into the annulus and to the formation of relatively tight ion pairs.37 Compound 5 was treated with propyl bromide (30 equiv) in acetone in the presence of Cs2CO3 (3 equiv). Cs2CO3, the nontemplate metal ion, was used to facilitate the rotation of the phenol unit. Compound 6 was then treated with Me3SiBr (2 equiv) to give PraBzloHaHo in 88% yield. This compound is classified as a di-0-substituted, optically active calix[4]arene with two different substituents (Table 111). Interestingly, the 1H N M R spectrum indicated that PraBzl@HaHoalso adopts a 1,3alternate conformation, although this conformation possesses a smaller number of intramolecular hydrogen bonds than a cone conformation. The foregoing synthetic studies indicate that a variety of new chiral 0-alkylation products from 1 can be designed, taking appropriate consideration of these synthetic strategies: (i) mono0-alkylation is achieved either by the adjustment of molar ratios of alkyl ha1ide:l and base:l or by the use of Ba(OH)2; (ii) K2CO3 in acetone can halt the reaction at the di-0-substituted stage; (iii) Na+ ion tends to suppress inversion of the phenol unit, whereas the Cs+ ion tends to facilitate it; (iv) Ba(OH)2is also useful for selectivesynthesis of tri-0-substituted calix[4]arenes with a cone conformation; and (v) a benzyl group is very useful not only as a substituent but also as a protecting group. Synthesis of Calix[4]arene-Based Diastereomers. Chiral calix[4]arenes may be optically resolved by an HPLC method using a chiral-packed column, but a more expeditious method is to convert them to diastereomers. Fortunately, some of the chiral calix[4]arenes listed in Tables I1 and I11 contain unsubstituted OH group(s) useful for further modifications. We thus synthesized a diastereomer 10 according to Scheme IV. Here we used calix[4]arene-25,26,27,28-tetrol(7)as the starting material instead of 1 because we later found that the reaction of alkyl halides with 7 can be stopped at each 0-alkylation stage more easily than the reaction with First, compound 7 was mono-0-propylated to yield 8. This compound was treated with benzyl bromide in the presence of K2CO3 to give di-0-substituted 9. This compound was treated with propyl bromide again in the presence of N a H to yield 10. Finally, the OH group in 10 was allowed to react with (-)-menthoxyacetyl chloride to yield diastereomer 11. We also used (S)-(+)-2-methylbutyryl chloride and N-@-tolylsulfonyl)L-phenylalanyl chloride to modify the residual OH group, but they did not yield ester derivatives probably because of steric hindrance. Compound 11 was subjected to HPLC separation using a conventional ODS column. Optical Resolution. In order to confirm that seven asymmetrically substituted compounds shown in Schemes 1-111 consist of a pair of enantiomers, we measured their IH N M R spectra in the presence of chiral shift reagents. We found that, among the several shift reagents tested,39Pirkle's reagent ((S)-2,2,2-trifluorol-(g-anthryl)ethanol) is most effective. In seven compounds the peaks split into pairs with a 1:l intensity ratio even at 25 OC. The cleanest split was observed for Pyl-containing calix[4]arenes. The finding suggests that Pirkle's reagent interacts via hydrogen bonding with the pyridine nitrogen of these calix[4]arenes. The (37)Grootenhuis, P. D. J.; Kollman, P. A,; Groenen, L. C.; Reinhoudt, D. N.; van Himmel, G. J.; Ugozzoli, F.; Andreetti, G. D. J . Am. Chem. SOC. 1990. 112. 4165. (38) Shimizu, H.; Iwamoto, K.; Shinkai, S. Unpublished results. (39)Chiral shift reagents tested herein are (S)-(-)-l,l'-bi-2-naphthol, (+)tris[ 3- [ (heptafluoropropyl)hydroxymethylene]camphorato]praseodymium(III), and Pirkle's reagent. Among them, Pirkle's reagent was the most effective.
Iwamoto et al.
4002 J. Am. Chem. Soc., Vol. 115, No. 10, 1993 Scheme IV OH
I)
KG03 Prl
11)
TMSl
8
7
K&Os Benzylbromide
9
10
11
-1
R E
Column Eiuent Flow rate
Sumipax OA 2000(8 0 x 300 mm) Hexane 2-Propanoi=98 2 viv 2 0 ml / min
Figure 2. Chromatogram for optical resolution of PruPraPylaHa. For separation conditions, see thedata given in the figure. Numbers recorded on the peaks are the retention times (t/min).
5.0
4 . 8 PPm
Figure 1. Partial ' H NMR spectra for the PylCH2 protons in PraPraM) at 30 OC in CDCI3: (A) racemic PraPraPylaHa; PyluHu(1.22 X (B) racemic PruPraPylaHuplus Pirkle's reagent (1.2 equiv); (C) (+)PruPraPylaHaplus Pirkle's reagent (1.2 equiv).
typical ' H NMRspectra observed for PpPraPylaHa in the absence and the presence of Pirkle's reagent are shown in Figure 1. We attempted the optical resolution of these racemic compounds by an HPLC method. We tested several chiral-packed columns (see the Experimental Section), but theoptical resolution was very difficult. The difficulty arose from the poor solubility
of these calix[4]arenes in organic solvents usable as the mobile phase.@ After much trial and error, we finally found that Pylcontaining calix[4]arenes could be resolved by Sumipax OA2000 (mobile phase: hexane:2-propanal = 98:2, v/v). We thus decided to isolate PraPraPylaHa(Figure 2). We divided the eluent into three fractions and recovered 50 mg of (+)-PruPruPylolHa from the first fraction and 20 mg of (-)-PraPraPyPHa from the third fraction from 120 mg of racemic PraPruPylaHa. Reexamination of these fractions with HPLC established that the purities of (+)- and (-)-PPPraPylaHa were 100% ee and 99.8% ee, respectively. The lH NMR spectrum of (+)-PraPraPylaHu in the presence of Pirkle's reagent is shown in Figure 1C. It is clear from this figure that in two sets of theOCHz(Py1) methylene protons the signals which appear at lower magnetic field are assigned to the (+) isomer. The CD spectra are shown in Figure 3. The symmetrical spectra indicate that these two compounds are optical isomers. The spectral data are summarized in Table IV. Compound (+)-PraPruPylaH*was heated in 1,1,2,2-tetrachloroethaneat 100 OC for 24 h, but thermal racemization through ring inversion did not take place, indicating the inhibition of oxygen-through-the-annulusrotation by Pr and Pyl substituents. We expected that diastereomer 11 could be separated by a conventional HPLC column. We found, however, that the separation factor of thesediastereomersis very low. Weconnected three ODS columns in series and obtained the chromatogram shown in Figure 4. We thus resolved 35 mg of lla from the first fraction and 25 mg of llb from the third fraction from 100 mg of diastereomeric 11. Reexamination of these isolated diastereomers with HPLC established that the purities of l l a and llb were 99.8% and 99.0%, respectively. The CD spectra are shown in Figure 5. Since lla and llb are diastereomeric compounds, they may not give symmetrical CD spectra. As shown in Figure 5 , however, the CD spectra are nearly symmetrical. Compound 12 corresponds to a phenyl unit bearing a (-)-menthoxyacetyl (40) Calix[4]arenes are soluble in halogen-containing solvents such as CHCl, and CH2CI2,but these solvents are not usable as a mobile phase for most of the above-mentioned chiral-packing columns.
Syntheses and Optical Resolution of Calix[4]arenes
J . Am. Chem. SOC.,Vol. 115, No. 10, 1993 4003 Column
-
m -6
u
1,
,
,
,'a**:,,-\
-8 250
300
350
,
6
~2 h
Figure 4. Chromatogram for resolution of diastereomeric 11. For separationconditions, see the data given in the figure. Numbers recorded on the peaks are the retention times (t/min). The peak at 56.02 min is assigned to unreacted IO (ca. 1%) 8
6
wavelength I nm
-
Figure 3. CD spectra of (+)- and (-)-Pr*Pr*PylaH* (solid and dotted lines, respectively) at 25 OC in hexane. Table IV. Spectral Parameters for Chiral Calix[4]arenes (25 "C) calix[4]arene [ c ~ ] ~ ~ / d e X,,,/nm g (+)-PrmPrmPylmHa +12.5" 254b 286b (-)-IO -7.35' 240d 282d 1la -27.7' 240d 218d llb -44.2? 240d 278d 12 -73.0' 231d
Eluent Flow rate Wavelength
Zorbax ODS(4 5 x 250 mm) three columns in series Methanol 0 6 ml mln 254nm
[8],,,/deg.cm2 dmol-I -4 1 OOb +6720b +5100d -6500d
+7800d +good
-7800d -9OOd -1 5 0 d
-
4 2
g o
U cu
-2
E -4 0 '
*
-6
0)
\
-0 0
m
(0
6
7
x
4 2
I?
c = 0.004, hexane. [(+)-Pr*Pr*Pyl*H"] = 1.22 X ? c = 1.00, chloroform. [ I l a or l l b ] = 5.00 X lo-) M,
lo] = 1.00 X lo-' M, [12] = 5.00 X
M, hexane. [(+)-IO or (-)-
M, acetonitrile.
group in 11. It only shows a weak, negative CD band at 231 nm (0 -150). Thus, the CD spectra of 11 are not related to the (-)-menthoxyacetyl-bearing phenyl unit but arise from the asymmetric deformation of the calix[4]arene ring. The nearly symmetrical C D spectra imply that lla and llb possess a nearly mirror-image structure.
12
The 'H N M R spectra of diastereomeric 11, lla, and llb are shown in Figure 6. It is seen from Figure 6A that the IH N M R spectrum of diastereomeric 11 is very complex. On the other hand, the 'H N M R spectra of lla and 1 lb are reasonably assigned to these compounds. The signals for the ArCHzAr methylene protons appear as four pairs of doublets at 3.0-3.4 and 4.0-4.5 ppm, indicating that lla and llb adopt cone conformations and have no planes of symmetry. Also, the multiplet resonance at 3.3-3.4 ppm in diastereomeric 11 changes to double triplets in lla and llb, indicating that this signal is assignable to the O C H methine proton in the (-)-menthoxy group. The most significant difference between lla and llb is seen for the signals of the OCH2CO methylene protons: lla gives a pair of doublets with
c n o u -2 -4 -6 -8 I
I
I
250
300 wavelength I nm
Figure 5. (A) CD spectra of I l a (first fraction) and l l b (third fraction) (solid and dotted lines, respectively) at 25 OC in acetonitrile. (B) CD spectra of (-)-lo and (+)-lo (solid and dotted lines, respectively) at 25 OC in acetonitrile.
a large chemical shift difference whereas llb gave a doublet resonance. (Basically, the OCHzCO methylene should appear as a pair of doublets in both lla and llb. As seen Figure 6, those in llb appear apparently as a doublet reasonance. We consider that the chemical shifts of these two protons are very close.) This suggests that the rotation of the (-)-menthoxy group in lla is more restricted than that in llb. We hydrolyzed lla and llb with tetramethylammonium hydroxide in THF. We recovered (-)-lo with the negative a value from lla and (+)-lo with the positive a value from llb. TheIHNMRspectraof (-)-and (+)-loin thepresenceofPirkle's reagent (30 OC, CDC13) show that these compounds are optical isomers with a purity higher than 99%. The CD spectra are shown in Figure 5 . The symmetrical spectra again support the idea that these two compounds are optical isomers. It is not yet clearwhy (-)-loand (+)-10giveexcitoncoupling-typeCDspectra and lla and llb do not. Conclusions In the present article, we systematically classified all chiral calix[4]arenes which can be obtained by 0-substitution and/or conformational isomerism. Of the 37 possible chiral calix[4]arenes, we have synthesized six chiral calix[4]arenes and optically
Iwamoto et al.
4004 J. Am. Chem. SOC.,Vol. 115, No. 10, 1993
A
5.0
4.0
3.0 ppm
Figure 6. Partial ' H NMR spectra for diastereomeric 11 (A), l l a (B), and l l b (C) at 30 OC in CDC13 (concentration, 2.0 X l e 3 M). The filled circles indicate the ArCH2Ar methylene protons, and the arrow indicates the OCH methine proton in the (-)-menthoxy group.
resolved two chiral calix[4]arenes, one by an HPLC method using a chiral-packed column and the other by the preparation of diastereomers. With such diversity of conformational isomerism and chirality in calix[4]arenes, we are reminded of carbohydrate chemistry. We therefore believe that the basic skeleton of chiral calix[4]arenes will provide the impetus for design of chiral host molecules, chiral synthons, chiral metal complexes, etc.
Experimental Section Materials. Preparations of the following compounds have been described: 5,11,17,23-tetra-rerr-butyI-25,26,27-trihydroxy-28-(~n~loxy)calix[4]arene (2),11Pr"PraPr@Bzla,llPraWP+Ha,I1PraPdBzlaHU,I1P P PrflHaH@," and 5,11,17,23-tetra-terl-butyl-25,27-dihydroxy-26,28(dibenzyloxy)calix[4]arene (5)." (To represent the stereoisomerism in calix[4]arene, we introduce here R I R ~ R for ~ R0-substituents ~ and CY and fl for phenyl inversion. For example, P P P P P P P P is a tetra-Opropylcalix[4]arene with a cone conformation and HaHaRlflR2flis a proximal R,,R2substituted 1,2-alternate calix [41arene.) 5,11,17,23-Tetra-tert-butyl-ZS,~27-trihydroxy-2&(2-pyri)calix[4Jareae (3). 5,11,17,23-Tetra-tert-butylcalix[4]arene-25,26,27,28-tetrol (1) (the crystal contains 1 mol of toluene, 1.0 g; 1.35 mmol), Ba(OH)2*8H20 (1.22 g, 3.85 mmol), and 2-(ch1oromethyl)pyridine hydrochloride (0.38 g, 2.31 mmol) were mixed in DMF (20 mL), and the reaction mixture was stirred for 22 h at room temperture under a nitrogen stream. The mixture was diluted with chloroform/water. The organic layer was separated, washed with water, and dried over MgS04. HPLC analysis (Zorbax ODS column, chloroform:methanol = 1:5, V/V) at this stage indicated that the solution contained 3 in 70% yield. The chloroform solution was evaporated to dryness, and the residue was recrystallized from chloroform/methanol: yield 54%, mp 274-276 OC; IR (Nujol) Y O H 3120 cm-I; ' H NMR (CDC13,25 OC, 400 MHz) 6 1.20, 1.21, and 1.22 (r-Bu, s each, 9 H, 18 H, and 9 H), 3.42, 3.44,4.24, and 4.49 (ArCHZAr, d each, J = 13.7 Hz for 3.42 and 4.24, J = 13.1 Hz for 3.44 and 4.49), 5.29 (OCH2, s, 2 H), 6.98, 7.04, 7.08, and 7.12 (ArH,
s,d,J=2.4Hz,s,d,J=2.4Hz,2Heach),7.31-8.69(pyridineprotons, m, 4 H), 9.53 and 10.10 (OH, broad s, 2 H and 1 H). Anal. Calcd for C&61N04: C, 81.15; H, 8.31; N , 1.89. Found: C, 80.98; H, 8.23; N, 2.10. 5,11,17,2fTeh.a-tert-butyl-25-hydroxy-26,27-dipropxy-28-( 2-pyridylmethoxy)calix[4]rene ( W W P y l a H a ) . Compound 3 (1 .O g, 1.35 mmol), Ba(OH)2.8H20 (1.68 g, 5.40 mmol), BaO (0.84 g, 5.40 mmol), and propyl bromide (0.49 mL, 5.40 mmol) were mixed in DMF (20 mL).
The reaction mixture was heated at 70 OC for 7 h under a nitrogen stream. The mixture was diluted with chloroform/water. The organic layer was separated, washed with water, and dried over MgS04. The chloroform solution was evaporated to dryness, the residue being recrystallized from methanol: yield 89%, mp 170-172 OC; IR (Nujol) Y O H 3155 cm-I; ' H NMR (CDCl,, 25 OC, 400 MHz) 6 0.81,0.86, 1.33, and 1.34 (I-Bu, s each, 9 H each), 0.61 and 1.10 (CH,, t each, 3 H each),
1.81-2.12(CCH2C,m,4H),3.16,3.20,3.23,3.28,4.22,4.34,4.43,and 4.47 (ArCHlAr, d each, J = 12.8 Hz for 3.16 and 4.47, J = 12.5 Hz for 3.20,3.23,4.34, and 4.43, and J = 13.3 Hz for 3.28 and 4.22, 1 H each), 3.70-3.84 (OCH2, m, 4 H), 4.93 and 5.01 (OCHz(Py1) methyleneprotons, d e a c h , J = 12.4Hz, 1 Heach), 5.59 (OH,s, 1 H),6.51,6.56,6.58,7.05, 7.08, 7.13,and 7.15 ( A r H , d e a c h , J = 2.4-2.7 H z , 2 H f o r 6 . 5 1 and 1 H for other ArH), 7.21-8.60 (pyridine protons, m, 4 H). Anal. Calcd for C56H69N04.0.5CH3OH: C, 81.16; H, 8.56; N, 1.67. Found: C, 81.29; H, 8.39; N, 1.61. The appearance of four inequivalent rerr-butyl groups and ArCH2Ar groups supports the view that this calix[4]arene has no plane of symmetry. 5,11,17,23-Tetra- tert-butyl-25,27-dihydroxy-26-( benzyloxy)-28-( 2pyridylmethoxy)cali~4~rene (4). Compound 3 (1.0 g, 1.35 mmol) was treated with benzyl chloride (1.55 mL, 13.5 mmol) in acetone in the presence of K2CO3 (1.87 g, 13.5 mmol). The reaction was continued for 24 h at reflux temperature under a nitrogen stream. The mixture was diluted with chloroform/water. Theorganic layer was separated, washed with water, anddriedover MgS04. HPLCanalysis (2orbaxODS column, ch1oroform:methanol = 1 3 , v/v) at this stage indicated that the solution contained 4 in 100% yield. The solution was evaporated to dryness, the residue being recrystallized from chloroform/methanol: yield 73%, mp 217-219 OC; IR (Nujol) YOH 3270 cm-I; ' H NMR (CDCI,,25 'C, 400 MHz) d 0.93, 0.94, and 1.30 (r-Bu, s each, 9 H, 9 H, and 18 H), 3.31, 3.32, 4.27, and 4.33 (ArCHzAr, d each, J = 13.1 Hz for all signals, 2 H each), 5.04 (OCHzAr, s, 2 H), 5.16 (OCHz(Py1) methylene protons, s, 2 H), 6.78, 6.80, and 7.07 (ArH, s, 2 H, 2 H, and 4 H), 7.21-8.58 (pyridine protons, m,4 H), 7.36-7.74 (ArH in Bzl, m, 5 H). Anal. Calcd for C57H68N04: C, 82.34; H, 8.25; N, 1.68. Found: C, 82.33; H, 8.09; N, 1.68. 5,11,17,23-Tetra-tert-butyl-25-hydroxy-26(bxy28-(2-pyridylmethoxy)calix[4larene (BzlaPPPylaHa). This compound was synthesized from 4 (0.3 g, 0.36 mmol), Ba(OH)r8H20 (0.454 g, 1.44 mmol),BaO (0.221 mg, 1.44 mmol), and propyl bromide (0.74 mL, 3.60 mmol) in DMF (20 mL). The reaction was continued for 1.5 h at 70 OC undera nitrogen stream. The workup was similar to that described for 3: yield 76%, mp 210-213 OC; IR (Nujol) YOH 3375 cm-I; 'HNMR (CDCI,, 25 OC, 400 MHz) 6 0.81,0.87, 1.33, and 1.34 (t-Bu, s each, 9
Syntheses and Optical Resolution of Calix[4]arenes H each), 0.26 (CH3, t, 3 H), 1.68-1.80 (CCH2C, m, 2 H), 3.11, 3.17, 3.24, 3.29, 4.32, 4.38, 4.39, and 4.43 (ArCHzAr, d each, J = 12.8 Hz for 3.17 and 4.38, J = 12.5 Hz for 3.1 1 and 4.32, J = 13.1 Hz for 3.24 and 4.43, and J = 13.4 Hz for 3.29 and 4.39, 1 H each), 3.60 (OCH2C, t, 2 H), 4.76 and 4.90 (OCH2Ar, d each, J = 11.0 Hz, 1 H each), 4.91 and 4.98 (OCHz(Py1) methylene protons, d each, J = 12.5 Hz, 1 H each), 5.50 (OH, s, 1 H), 6.52, 6.59, 7.07, 7.08, 7.12, and 7.13 (ArH, m, 2 H, 2 H, 1 H, 1 H, 1 H, and 1 H), 7.20-8.58 (pyridine protons, m, 4 H), 7.33-7.54 (ArH in Bzl, m,5 H). Anal. Calcd for C60H73N04: C, 82.62; H, 8.44; N, 1.61. Found: C, 82.12; H, 8.28; N, 1.51.
5,11,17,23-Tetra-tert-butyl-25-hydroxy-26,28-(dibenzyloxy)-27propoxycalix[4]arene (6). Compound 5 (1.0 g, 1.21 mmol) was treated with propyl bromide (3.68 mL, 40.5 mmol) in acetone (25 mL) in the presence of Cs2CO3 (1.32 g, 4.05 mmol). The reaction mixture was refluxed under a nitrogen stream for 22 h. The mixture was diluted with chloroform/water. The organic layer was washed with water, dried over MgS04, and concentrated to dryness. The residue was recrystallized fromchloroform/methanol: yield 76%, mp 209-21 1 "C; IR (Nujol) Y O H 3310 cm-I; IH NMR (CDCI3, 25 OC, 400 MHz) 8 0.99, 1.18, and 1.29 (?-Bu,seach,9H, 18H,and9H),O.O4(CH3,t,3H), 1.11-1.25(CCH2C, m, 2 H), 2.34 (OCHlC, t, 2 H), 3.1 1 and 4.01 (ArCHzAr, d each, J = 12.8 Hz, 2 H each), 3.90 (ArCH2Ar, s, 4 H), 4.74 and 5.17 (OCHzAr, d, J = 11.9 Hz, 2 H each), 6.80 (OH, s, 1 H), 6.95 and 7.04 (ArH, d, J = 2.6Hz,ZHeach),7.01 and7.12(ArH,s,ZHeach),7.34-7.48(ArH in Bzl, m, 10 H). Anal. Calcd for C61H7404:C, 84.09; H, 8.56. Found: C, 83.91; H, 8.14. The splitting pattern of the ArCH2Ar methylene protons and the upfield shift of the signals for the propyl protons indicate that 6adopts a partial-cone conformation and the propyl group is inverted.
J. Am. Chem. Soc.. Vol. 115, No. 10, 1993 4005 25,27-Dihydroxy-26-propoxy-2S-(benzyloxy)cali~4]arene (9). 25,26,27-Trihydroxy-28-propxycaliu[4]arene(2.35 g, 5.0 mmol)was treated with benzyl bromide (0.7 mL, 5.8 mmol) in DMF at 70 OC under a nitrogen stream in the presence of K2C03 (1.38 g, 10.0 mmol). The progress of the reaction was monitored by an HPLC method (Zorbax ODS, ch1oroform:methanol = 1:5, v/v). The reaction was stopped after 8 h by the addition of an aqueous 1 M HC1 solution (50 mL). After cooling, the aqueous solution was extracted with chloroform (200 mL). The organic layer was separated, washed with an aqueous 1 M HCl solution, an aqueous sodium thiosulfate solution, and aqueous NaCIsaturated solution, and dried over MgS04. After filtration the solution was concentrated to dryness. The residue (white powder) was recrystallized from chloroform/methanol: yield 72%, mp 231-233 OC; IR (Nujol) YOH 3380, YCOC 1200 cm-I; IH NMR (CDC13,25 OC, 60 MHz)
61.22(CH3,t,3H),2.04(CCH2C,m,ZH),3.35,4.30,and4.36(ArCH2-
Ar, d each, J = 12.9 Hz for all peaks, 4 H, 2 H, and 2 H), 3.45 (OCH2 in Pr, t, 2 H), 5.06 (OCH2 in benzyl, s, 2 H), 6.62-7.80 (ArH, m, 17 H), 8.07 (OH, s, 2 H). Anal. Calcd for C38H3604: C, 81.98; H, 6.51. Found: C, 81.60; H, 6.42. 25-Hydroxu-~27-~pr~ipropoxy-28-(benyloxy)ce (10). Compound 9 (1.20 g, 2.15 mmol)was treated with oil-dispersed NaH (90 mg, 2.25 mmol) in DMF (100 mL) at 0 OC under a nitrogen stream. After 15 min propyl bromine (0.22 mL, 2.25 mmol) was added, and the progress of the reaction was monitored by an HPLC method (Zorbax ODS, ch1oroform:methanol = 1:5, v/v). The HPLC peak for 10 became the maximum after 24 h. Unreacted NaH was decomposed by a few drops of methanol, and the reaction was stopped here by the addition of an aqueous 1 M HCI solution (25 mL). The solution was extracted with chloroform (100 mL). The organic layer was separated, washed with an 5,11,17~Tetre-tert-buty~-25,26-dihydroxy-27-~~~~(~b~)aqueous 1 M HCI solution, an aqueous sodium thiosulfate solution, and calix[4]arene (Pr"Bzl6H"HB). One of the two benzyl groups was an aqueous NaCI-saturated solution, and dried over MgS04. After deprotected by treatment of 6 (0.50 g, 0.57 mmol) with Me3SiBr (0.151 filtration the solution was concentrated to dryness. The residue (yellow mL, 1.14 mmol)in chloroform (25 mL) for 2 h a t room temperature. The oil) was subjected to preparative thin-layer chromatography (silica gel, workup method was reported previous1y:Il yield 88%, mp 173-174 "C; hexane:chloroform = 1:1, v/v). We collected the fraction with Rf = IR (Nujol) YOH 3350 cm-]; ' H NMR (CDCl3,25 OC, 400 MHz) 6 0.81, 0.58. The recovered product (white powder) was recrystallized from 0.85, 1.41, and 1.43 (t-Bu, s each, 9 H each), 0.71 (CHI, t, 3 H), 1.44chloroform/methanol: yield 72%, mp 138-140 OC; IR (Nujol) Y O H 3400, 1.58 (CCH2C,m,2H),3.52,3.61,3.87,4.02,4.09,and4.15 (ArCHzAr, YCOC 1090, 1200 cm-I; IH NMR (CDC13,30 "C, 400 MHz) 8 0.67 and d e a c h , J = 13.1Hzfor3.52and4.15,J=14.0Hzfor3.61and4.02, and J = 16.0 Hz for 3.87 and 4.09, 1 H each), 4.05 (ArCHzAr, broad 1.08 (CHI, teach, 3 H each), 1.87 and 2.05 (CCH2C, m each, 2 H each), 3.14, 3.19, 3.27, 3.30, 4.35, 4.38, 4.41, and 4.47 (ArCHzAr, d each, J s, 2 H), 3.50-3.74 (OCH2, m,2 H), 4.27 and 4.34 (OCH2Ar, d each, = 13.4Hzfor3.14,3.19,3.27,4.35,4.38,and4.41a n d J = 13.7Hzfor J = 12.4 Hz, 1 H each), 5.78-6.76 (ArH in benzyl, m,5 H), 6.70,6.72, 3.30 and 4.47, 1 H each), 3.72 (OCH2 in propyl, m,4 H), 4.68 (OH, s, 6.86,7.00,7.15,7.16,7.24,and7.32 (ArH,deach,J= 2.4 Hz, 1 Heach), 1 H), 4.81 (OCH2 in benzyl, dd, 2 H), 6.3-7.5 (ArH, m, 17 H). Anal. 8.00 and 9.09 (OH, s each, 1 H each). Anal. Calcd for C54H6804: C, Calcd for C41H4204: C, 82.20; H, 7.07. Found: C, 82.25; H, 7.30. The 83.03; H, 8.56. Found: C, 82.91; H, 8.22. appearance of four inequivalent ArCH2Ar methylene groups in a pair of 25,26,27-Trihydroxy-ZS-propxycalixI4]are(8).Calix[4]arene-25,doublets supports the view that 9 adopts a cone conformation and has no 26,27,28-tetrol(7) (10.0 g, 23.6 mmol) was treated with propyl bromide plane of symmetry. (1 8.2 mL, 200 mmol)in anhydrated DMF (300 mL) at room temperature under the anaerobic conditions in the presence of Ba(OH)24H20 (14.2 25-[(-)-Menthoxyacetoxy~26,27-dipro~x~~-(benzyloxy)calix[4]g, 45.0 mmol) and BaO (13.8 g, 90.0 mmol). The reaction was stopped arene (11). Compound 10 (0.60 g, 1.0 mmol) was treated with oilafter 24 h by addition of aqueous 1.0 M HCI (100 mL). The solution dispersed NaH (80 mg, 2.0 mmol) in DMF (2 mL)/THF (20 mL) at 0 "C under a nitrogen stream. After 30 min (-)-menthoxyacetyl chloride wasextracted withchloroform (300 mL). Theorganiclayer was separated (0.35 g, 1.5 mmol) was added. After 3 h, 10 was no longer detected by and washed with aqueous 1.OM HCl, aqueous sodium thiosulfate solution, HPLC (Zorbax ODS, ch1oroform:methanol= 1:5,v/v). UnreactedNaH and saturated NaCl solution (three times). The solution was dried over MgS04. Concentration under reduced pressure yielded a white powder was decomposed by a few drops of methanol, and thereaction was stopped containing 25,27-dihydroxy-26,28-dipropoxycalix[4]arene(95% purity) by addition of an aqueous 1 M HCI solution (20 mL). The solution was extracted with chloroform (100 mL). The organic layer was separated, in quantitative yield. We recrystallized the small amount from chloroform/methanol for analysis: mp 262-264 OC; IR (KBr) Y O H 3250, washed three times with water, and dried over MgS04. After filtration the solution was concentrated to dryness. The residue (yellow oil) was YCOC 1200 cm-I; ' H NMR (CDC13,25 OC, 60 MHz) 6 1.28 (CHI, t, 6 crystallized from chloroform/ethanoE yield 80%, mp 141-143 OC; IR H), 2.04 (CCH2C, m, 4 H), 3.36 and 4.34 (ArCH2Ar, d each, 4 H each), 3.96(OCH2,t,4H),6.56-7.20(ArH,m, 12H),8.29(OH,s,2H).Anal. (Nujol) YOH 1760, YCW 1120,1200 cm-I; ' H NMR (CDC13,30 OC, 400 Calcd for C37H4204: C, 80.36; H, 7.14. Found: C, 80.28; H, 7.13. The MHz) 8 0.81-2.58 (menthyl protons and C H I C H ~in propyl, m, 56 H), result indicates that the reaction in the presence of Ba(OH)2 at the reflux 3.00, 3.02. 3.12, 3.17, 3.20, 3.98, 4.01, 4.05, 4.07, 4.40, 4.49, and 4.50 temperature yields tri-0-substituted calix whereas at (ArCHzAr,deach,J= 13.1Hzfor3.00,3.02,3.12,4.40,4.49,and4.50, room temperature it yields di-0-substituted calix[4]arenes. J = 13.4 Hz for 3.17 and 4.05, and J = 14.7 Hz for 3.20, 3.98, and 4.01, 2H,1H,1H,2H,2H,1H,1H,1H,1H,2H,1H,and1H),3.33 The white powder was dissolved in anhydrated chloroform (200 mL) (OCH in menthyl, m, 2 H), 3.69 and 3.95 (OCH2 in propyl, m each, 4 and treated with MeISiI (3.4 mL, 24.9 mmol) at reflux temperature. H each), 4.80 and 4.81 (OCHzAr, dd, 2 H each), 4.88 and 4.92 (OCH2After 18 h, the reaction was stopped by addition of an aqueous 3.0 M CO, dd, 2 H each), 6.35-7.35 (ArH, m,34 H) (the IH NMR spectrum HCI solution. The organic layer was separated and washed with aqueous of diastereomeric 11 was very complex but could be assigned basically sodium thiosulfate solution and saturated NaCl solution (three times). as duplicate signals of each diastereomer). Anal. Calcd for C53H6206: The solution was dried over MgS04. The solution was evaporated to C, 80.06; H, 7.86. Found: C, 79.93; H, 7.88. dryness, the solid residue being recrystallized from chloroform/methanol: yield (from 7) 7876, mp 264-266 OC; IR (Nujol) Y O H 3190 and 2,dDimethylphenyl (-)-Menthoxyacetate (12). To a THF solution 3320, YCOC 1090 and 1180 cm-I; IH NMR (CDCl,, 30 OC, 60 MHz) 8 (25 mL) containing 2,6-dimethylphenol (0.47 g, 3.84 mmol) and 1.24 (CH3, t, 3 H), 2.1 1 (CCH2C. m, 2 H), 3.43,4.28, and 4.38 (ArCH2triethylamine (2.0mL, 9.88 mmol) wasadded (-)-menthoxyacetylchloride Ar, d each, 4 H, 2 H, and 2 H), 4.1 1 (OCH2, t, 2 H), 6.25-7.10 (ArH, dropwise from a microsyringe. The reaction was continued at 0 OC for m, 12 H), 9.38 and 9.69 (OH, s each, 2 H and 1 H). Anal. Calcd for 12 h. The reaction was stopped by the addition of an aqueous 1 M HCI C ~ I H ~ O O ~ C HC, ~ O77.33; H : H, 6.64. Found: C, 77.65; H, 6.32. solution (20 mL). The solution was extracted with chloroform (100 mL).
4006 J. Am. Chem. SOC.,Vol. 1 1 5, No. IO, 1993 The organic layer was separated, washed three times with an aqueous NaC1-saturated solution, and dried over MgS04. After filtration the solution was concentrated to dryness. The residue (yellow oil) was subjected to column chromatography (silica gel, hexane:ethyl acetate = 8:l,v/v): slightly yellow oil, yield 72%; IR (Nujol) YOH 1750, YCW 1100, 1170 cm-I; IH NMR (CDCl,, 25 "C, 250 MHz) 6 0.81-2.3 (methyl protons, m, 18 H), 2.15 (ArCH,, s, 6 H), 3.28 (OCH, 2t, 1 H), 4.42 (OCH2, 2d, 2 H), 7.05 (ArH, s, 3 H). Anal. Calcd for C20H3003: C, 75.43; H, 9.49. Found: C, 75.48; H, 9.35. Optical Resolution. In order to optically resolve racemates, we tested six chiral-packed HPLC columns: Daicel chiralpak OP and AD, Sumitomo Sumipax OA 2000 and OA 3100, Merck Chiraspher, and YMC-Pac KO3. Among several asymmetrically substituted calix[4]arenes, we found that Sumipax OA 2000 is useful for optical resolution of Pr"Pr*PyPH" (mobile phase, hexane:2-propanol= 98:2, v/v). On the other hand, we could not find any chiral-packed HPLC column suitable fortheopticalresolutionof 10. Wethusconverted lototheesterderivative with (-)-menthylacetyl chloride, and the resultant diastereomers 11were isolated by a conventional HPLC method (Zorbax ODS column, 4.5 X 250 mm, three columns in series; mobile phase, methanol). We divided the eluent into three fractions and recovered one optical isomer from the first fraction and another optical isomer from the third fraction. Optically resolved PruPruPylaHu: from the first fraction, mp 136-137 "C (note that this mp is lower than that for racemic PraPra-
Iwamoto et al. Pyl"H"(mp 170-172 "C)),recovery42%, lOO%ee(fromHPLCanalysis); from the third fraction, mp 130-134 "C, recovery 17%, 99.8% ee (from HPLC analysis). Optically resolved 11: from the first fraction, mp 138139 "C, recovery 35%,diastereomericpurity99.8%(fromHPLCanalysis); from the third fraction, mp 161-163 "C, recovery 25%, diastereomeric purity 99.0% (from HPLC analysis). Hydrolysis of Optically Resolved 11 to 10. Optically resolved 11 (30 mg, 0.04 mmol) in THF (25 mL) was treated with aqueous 10% tetramethylammonium hydroxide solution (10mL) at reflux temperature. Thereaction was followed by anHPLC method (ZorbaxODS,chloroform: methanol = 1 5 , v/v): the HPLC peak for 11 disappeared after 24 h, After cooling, the solution was neutralized with an aqueous 3 M HC1 solution (25 mL). The aqueous solution was extracted with chloroform (50 mL). The organic layer was separated, washed with an aqueous NaC1-saturated solution, and dried over MgS04. After filtration, the filtrate was evaporated to dryness. Crystallization of the slightly yellow, oily residue from chloroform/methanol gave white crystals: mp 97-99 "C (note that this melting point is lower than that for racemic 10 (mp 138-140 "C)), yield 8096,higher than 9 9 % (from ~ IH NMRspectroscopy with Pirkle's reagent).
Acknowledgment. This research was supported in part by a grant from the Ministry of Education of Japan. We thank Dr. T. James (JRDC, ChemirecognicsProject) for helpful discussions.
